tbuckley/cabot-search huggingface dataset:
<i>In vivo</i> nanoparticle-based T cell imaging can predict therapy response towards adoptive T cell therapy in experimental glioma
Authors: Jessica Hunger, Katharina Schregel, Berin Boztepe, Dennis Alexander Agardy, Verena Turco, Kianush Karimian-Jazi, Ina Weidenfeld, Yannik Streibel, Manuel Fischer, Volker Sturm, Rachel Santarella-Mellwig, Michael Kilian, Kristine Jähne, Katharina Sahm, Wolfgang Wick, Lukas Bunse, Sabine Heiland, Theresa Bunse, Martin Bendszus, Michael Platten, Michael O. Breckwoldt
Journal: Theranostics (2023)

Rationale: Intrinsic brain tumors, such as gliomas are largely resistant to immunotherapies including immune checkpoint blockade. Adoptive cell therapies (ACT) including chimeric antigen receptor (CAR) or T cell receptor (TCR)-transgenic T cell therapy targeting glioma-associated antigens are an emerging field in glioma immunotherapy. However, imaging techniques for non-invasive monitoring of adoptively transferred T cells homing to the glioma microenvironment are currently lacking. Methods: Ultrasmall iron oxide nanoparticles (NP) can be visualized non-invasively by magnetic resonance imaging (MRI) and dedicated MRI sequences such as T2* mapping. Here, we develop a protocol for efficient ex vivo labeling of murine and human TCR-transgenic and CAR T cells with iron oxide NPs. We assess labeling efficiency and T cell functionality by flow cytometry and transmission electron microscopy (TEM). NP labeled T cells are visualized by MRI at 9.4 T in vivo after adoptive T cell transfer and correlated with 3D models of cleared brains obtained by light sheet microscopy (LSM). Results: NP are incorporated into T cells in subcellular cytoplasmic vesicles with high labeling efficiency without interfering with T cell viability, proliferation and effector function as assessed by cytokine secretion and antigen-specific killing assays in vitro. We further demonstrate that adoptively transferred T cells can be longitudinally monitored intratumorally by high field MRI at 9.4 Tesla in a murine glioma model with high sensitivity. We find that T cell influx and homogenous spatial distribution of T cells within the TME as assessed by T2* imaging predicts tumor response to ACT whereas incomplete T cell coverage results in treatment resistance. Conclusion: This study showcases a rational for monitoring adoptive T cell therapies non-invasively by iron oxide NP in gliomas to track intratumoral T cell influx and ultimately predict treatment outcome.
Visualizing vasculature and its response to therapy in the tumor microenvironment
Authors: Qiaoya Lin, Peter L. Choyke, Noriko Sato
Journal: Theranostics (2023)

Tumor vasculature plays a critical role in the progression and metastasis of tumors, antitumor immunity, drug delivery, and resistance to therapies.The morphological and functional changes of tumor vasculature in response to therapy take place in a spatiotemporal-dependent manner, which can be predictive of treatment outcomes.Dynamic monitoring of intratumor vasculature contributes to an improved understanding of the mechanisms of action of specific therapies or reasons for treatment failure, leading to therapy optimization.There is a rich history of methods used to image the vasculature.This review describes recent advances in imaging technologies to visualize the tumor vasculature, with a focus on enhanced intravital imaging techniques and tumor window models.We summarize new insights on spatial-temporal vascular responses to various therapies, including changes in vascular perfusion and permeability and immune-vascular crosstalk, obtained from intravital imaging.Finally, we briefly discuss the clinical applications of intravital imaging techniques.
PET imaging of focused-ultrasound enhanced delivery of AAVs into the murine brain
Authors: Javier Ajenjo, Jai Woong Seo, Josquin Foiret, Bo Wu, Marina Nura Raie, James Wang, Brett Zain Fite, Nisi Zhang, Rim Malek, Corinne Beinat, Noeen Malik, David Alexander Anders, Katherine W. Ferrara
Journal: Theranostics (2023)

Rationale: Despite recent advances in the use of adeno-associated viruses (AAVs) as potential vehicles for genetic intervention of central and peripheral nervous system-associated disorders, gene therapy for the treatment of neuropathology in adults has not been approved to date.The currently FDA-approved AAV-vector based gene therapies rely on naturally occurring serotypes, such as AAV2 or AAV9, which display limited or no transport across the blood-brain barrier (BBB) if systemically administered.Recently developed engineered AAV variants have shown broad brain transduction and reduced off-target liver toxicity in non-human primates (NHPs).However, these vectors lack spatial selectivity for targeted gene delivery, a potentially critical limitation for delivering therapeutic doses in defined areas of the brain.The use of microbubbles, in conjunction with focused ultrasound (FUS), can enhance regional brain AAV transduction, but methods to assess transduction in vivo are needed.Methods: In a murine model, we combined positron emission tomography (PET) and optical imaging of reporter gene payloads to non-invasively assess the spatial distribution and transduction efficiency of systemically administered AAV9 after FUS and microbubble treatment.Capsid and reporter probe accumulation are reported as percent injected dose per cubic centimeter (%ID/cc) for in vivo PET quantification, whereas results for ex vivo assays are reported as percent injected dose per gram (%ID/g).Results: In a study spanning accumulation and transduction, mean AAV9 accumulation within the brain was 0.29 %ID/cc without FUS, whereas in the insonified region of interest of FUS-treated mice, the spatial mean and maximum reached ~2.3 %ID/cc and 4.3 %ID/cc, respectively.Transgene expression assessed in vivo by PET reporter gene imaging employing the pyruvate kinase M2 (PKM2)/[ 18 F]DASA-10 reporter system increased up to 10-fold in the FUS-treated regions, as compared to mice receiving AAVs without FUS.Systemic injection of AAV9 packaging the EF1A-PKM2 transgene followed by FUS in one hemisphere resulted in 1) an average 102-fold increase in PKM2 mRNA concentration compared to mice treated with AAVs only and 2) a 12.5-fold increase in the insonified compared to the contralateral hemisphere of FUS-treated mice. Conclusion:Combining microbubbles with US-guided treatment facilitated a multi-hour BBB disruption and stable AAV transduction in targeted areas of the murine brain.This unique platform has the potential to provide insight and aid in the translation of AAV-based therapies for the treatment of neuropathologies.
Upregulated FOXM1 stimulates chondrocyte senescence in Acot12<sup>-/-</sup>Nudt7<sup>-/-</sup> double knockout mice
Authors: Jinsoo Song, Ee Hyun Kim, Jun-Ho Yang, Donghyeon Kim, Akhmad Irhas Robby, Se-ah Kim, Sung Young Park, Ji Hyun Ryu, Eun-Jung Jin
Journal: Theranostics (2023)

Rationale: One of the hallmarks of osteoarthritis (OA), the most common degenerative joint disease, is increased numbers of senescent chondrocytes.Targeting senescent chondrocytes or signaling mechanisms leading to senescence could be a promising new therapeutic approach for OA treatment.However, understanding the key targets and links between chondrocyte senescence and OA remains unclear.Methods: Senescent chondrocytes were identified from Nudt7 -/-, Acot12 -/-, double-knockout mice lacking Acot12 and Nudt7 (dKO) and applied to microarray.The presence of forkhead transcription factor M1 (FOXM1) was detected in aged, dKO, and destabilization of the medial meniscus (DMM) cartilages and articular chondrocytes, and the effect of FoxM1 overexpression and acetyl-CoA treatment on cartilage homeostasis was examined using immunohistochemistry, quantitative real-time PCR (qRT-PCR), cell apoptosis and proliferation assay, and safranin O staining.Delivery of Rho@PAA-MnO2 (MnO2 nanosheet) or heparin-ACBP/COS-GA-siFoxM1 (ACBP-siFoxM1) nanoparticles into DMM cartilage was performed.Results: Here, we propose the specific capture of acetyl-CoA with the delivery of (FoxM1 siRNA (siFoxM1) to prevent cartilage degradation by inhibiting the axis of chondrocyte senescence.dKO stimulate chondrocyte senescence via the upregulation of FoxM1 and contribute to severe cartilage breakdown.We found that the accumulation of acetyl-CoA in the dKO mice may be responsible for the upregulation of FoxM1 during OA pathogenesis.Moreover, scavenging reactive oxygen species (ROS) induced by chondrocyte senescence via the implantation of MnO2 nanosheets or delivery of siFoxM1 functionalized with acetyl-CoA binding protein (ACBP) to capture acetyl-CoA using an injectable bioactive nanoparticle (siFoxM1-ACBP-NP) significantly suppressed DMM-induced cartilage destruction. Conclusion:We found that the loss of Acot12 and Nudt7 stimulates chondrocyte senescence via the upregulation of FoxM1 and accumulation of acetyl-CoA, and the application of siFoxM1-ACBP-NP is a potential therapeutic strategy for OA treatment.
MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1
Authors: Chen Zhang, Weilong Ye, Mengyao Zhao, Lujue Long, Dengsheng Xia, Zhipeng Fan
Journal: International Journal of Oral Science (2023)

Mesenchymal stem cell (MSC)-based therapy has emerged as a promising treatment for spinal cord injury (SCI), but improving the neurogenic potential of MSCs remains a challenge. Mixed lineage leukemia 1 (MLL1), an H3K4me3 methyltransferases, plays a critical role in regulating lineage-specific gene expression and influences neurogenesis. In this study, we investigated the role and mechanism of MLL1 in the neurogenesis of stem cells from apical papilla (SCAPs). We examined the expression of neural markers, and the nerve repair and regeneration ability of SCAPs using dynamic changes in neuron-like cells, immunofluorescence staining, and a SCI model. We employed a coimmunoprecipitation (Co-IP) assay, real-time RT-PCR, microarray analysis, and chromatin immunoprecipitation (ChIP) assay to investigate the molecular mechanism. The results showed that MLL1 knock-down increased the expression of neural markers, including neurogenic differentiation factor (NeuroD), neural cell adhesion molecule (NCAM), tyrosine hydroxylase (TH), βIII-tubulin and Nestin, and promoted neuron-like cell formation in SCAPs. In vivo, a transplantation experiment showed that depletion of MLL 1 in SCAPs can restore motor function in a rat SCI model. MLL1 can combine with WD repeat domain 5 (WDR5) and WDR5 inhibit the expression of neural markers in SCAPs. MLL1 regulates Hairy and enhancer of split 1 (HES1) expression by directly binds to HES1 promoters via regulating H3K4me3 methylation by interacting with WDR5. Additionally, HES1 enhances the expression of neural markers in SCAPs. Our findings demonstrate that MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1. These results provide a potential therapeutic target for promoting the recovery of motor function in SCI patients.
Clinical Courses and Outcome in Patients with Blast Injuries: An Observational Case Series Study
Authors: Anshu Singh, Anshu Singh, Ravi Kumar, Sandhya Pandey, Vijay Kumar
Journal: International Journal of Surgery (2023)

Background: Blast injuries are similar to any other burn injuries. Emphasis is given to safety measures as the treatment of burns is a painful and prolonged process that involves a loss of limb or sensory organs with a lot of expenditure. Aim: To evaluate the patient with their outcomes and management who sustained blast injuries. Patients and Methods: All patients who had blast injuries with different kinds and mechanisms were prospectively studied and clinical presentation, management and outcomes were reviewed. Results: 6 patients were studied with different age groups and different mechanisms of blast injuries of which one was female who sustained thermal injuries associated with AC Blast, two patients sustained explosive blast, and others were involved in methanol cylinder blast, improvised explosive device and mixing fertilizer as a chemical form of blast injuries respectively. All were managed and the outcome was satisfactory for 2 individuals, 3 sustained amputations and 1 sustained mortality. Conclusion: The high energy wave produced during blasts are strong enough to produce fatal injuries that will lead to high morbidity and mortality. Civilians should be aware and personal protective equipment should be worn by those who are indulged in this hazardous occupation.
The strategies to cure cancer patients by eradicating cancer stem-like cells
Authors: Yansui Mai, Jiyan Su, Chuan Yang, Chenglai Xia, Liwu Fu
Journal: Molecular Cancer (2023)

Abstract Cancer stem-like cells (CSCs), a subpopulation of cancer cells, possess remarkable capability in proliferation, self-renewal, and differentiation. Their presence is recognized as a crucial factor contributing to tumor progression and metastasis. CSCs have garnered significant attention as a therapeutic focus and an etiologic root of treatment-resistant cells. Increasing evidence indicated that specific biomarkers, aberrant activated pathways, immunosuppressive tumor microenvironment (TME), and immunoevasion are considered the culprits in the occurrence of CSCs and the maintenance of CSCs properties including multi-directional differentiation. Targeting CSC biomarkers, stemness-associated pathways, TME, immunoevasion and inducing CSCs differentiation improve CSCs eradication and, therefore, cancer treatment. This review comprehensively summarized these targeted therapies, along with their current status in clinical trials. By exploring and implementing strategies aimed at eradicating CSCs, researchers aim to improve cancer treatment outcomes and overcome the challenges posed by CSC-mediated therapy resistance.
Regulation and signaling pathways in cancer stem cells: implications for targeted therapy for cancer
Authors: Zhen Zeng, Minyang Fu, Yuan Hu, Yuquan Wei, Xiawei Wei, Min Luo
Journal: Molecular Cancer (2023)

Abstract Cancer stem cells (CSCs), initially identified in leukemia in 1994, constitute a distinct subset of tumor cells characterized by surface markers such as CD133, CD44, and ALDH. Their behavior is regulated through a complex interplay of networks, including transcriptional, post-transcriptional, epigenetic, tumor microenvironment (TME), and epithelial-mesenchymal transition (EMT) factors. Numerous signaling pathways were found to be involved in the regulatory network of CSCs. The maintenance of CSC characteristics plays a pivotal role in driving CSC-associated tumor metastasis and conferring resistance to therapy. Consequently, CSCs have emerged as promising targets in cancer treatment. To date, researchers have developed several anticancer agents tailored to specifically target CSCs, with some of these treatment strategies currently undergoing preclinical or clinical trials. In this review, we outline the origin and biological characteristics of CSCs, explore the regulatory networks governing CSCs, discuss the signaling pathways implicated in these networks, and investigate the influential factors contributing to therapy resistance in CSCs. Finally, we offer insights into preclinical and clinical agents designed to eliminate CSCs.
Florida loses legal battle to keep covid data secret
Authors: Owen Dyer
Journal: BMJ (2023)

The state government of Ron DeSantis in Florida, which manipulated covid data to show deaths falling during a surge, has agreed to release old data and to publish new covid data, abandoning a two year legal battle to keep the data secret.Although the state continues to deny wrongdoing, Florida's Department of Health agreed in an out-of-court settlement to pay the $152 000 legal fees of its opponents, which include a former Democratic congressman, the Florida Center for Government Accountability, the First Amendment Foundation, and several media outlets including the Associated Press, Miami Herald, and Washington Post.Florida initially maintained a daily pandemic dashboard giving vital daily data on infections, hospital admissions, and deaths, but in June 2021, during a lull in cases, it was one of several Republican governed states to scale back its reporting, moving from daily to weekly reports.
Gain-of-Function p53 Mutation Acts as a Genetic Switch for TGFβ Signaling–Induced Epithelial-to-Mesenchymal Transition in Intestinal Tumors
Authors: Dong Wang, Mizuho Nakayama, Chang Pyo Hong, Hiroko Oshima, Masanobu Oshima
Journal: Cancer Research (2023)

Abstract Signaling by TGFβ family cytokines plays a tumor-suppressive role by inducing cell differentiation, while it promotes malignant progression through epithelial-to-mesenchymal transition (EMT). Identification of the mechanisms regulating the switch from tumor suppression to tumor promotion could identify strategies for cancer prevention and treatment. To identify the key genetic alterations that determine the outcome of TGFβ signaling, we used mouse intestinal tumor-derived organoids carrying multiple driver mutations in various combinations to examine the relationship between genotypes and responses to the TGFβ family cytokine activin A. KrasG12D mutation protected organoid cells from activin A–induced growth suppression by inhibiting p21 and p27 expression. Furthermore, Trp53R270H gain-of-function (GOF) mutation together with loss of wild-type Trp53 by loss of heterozygosity (LOH) promoted activin A–induced partial EMT with formation of multiple protrusions on the organoid surface, which was associated with increased metastatic incidence. Histologic analysis confirmed that tumor cells at the protrusions showed loss of apical–basal polarity and glandular structure. RNA sequencing analysis indicated that expression of Hmga2, encoding a cofactor of the SMAD complex that induces EMT transcription factors, was significantly upregulated in organoids with Trp53 GOF/LOH alterations. Importantly, loss of HMGA2 suppressed expression of Twist1 and blocked activin A–induced partial EMT and metastasis in Trp53 GOF/LOH organoids. These results indicate that TP53 GOF/LOH is a key genetic state that primes for TGFβ family-induced partial EMT and malignant progression of colorectal cancer. Activin signaling may be an effective therapeutic target for colorectal cancer harboring TP53 GOF mutations. Significance: KRAS and TP53 mutations shift activin-mediated signaling to overcome growth inhibition and promote partial EMT, identifying a subset of patients with colorectal cancer that could benefit from inhibition of TGFβ signaling.
Why there is new hope for the care of chronic diseases in Africa
Authors: Matshidiso Moeti, Ana Mocumbi, Gene Bukhman
Journal: BMJ (2023)

The PEN-plus strategy aims to improve access and care for non-communicable diseases in rural, low income areas and could revolutionise the care of chronic diseases in Africa, write <b>Matshidiso Moeti</b>, <b>Ana Mocumbi</b>, and <b>Gene Bukhman</b>
Combined effect of ozone and household air pollution on COPD in people aged less than 50 years old
Authors: Zhenzhen Xing, Ting Yang, Su Shi, Xia Meng, Di Chai, WeiMing Liu, Yaqi Tong, Yuxia Wang, Yali Ma, MingMing Pan, Jia Cui, Huanyu Long, Tieying Sun, Renjie Chen, YanFei Guo
Journal: Thorax (2023)

Objectives Air pollution has been suggested as an important risk factor for chronic obstructive pulmonary disease (COPD); however, evidence of interactive effects on COPD between different factors was sparse, especially for young adults. We aimed to assess the combined effects of ambient ozone (O 3 ) and household air pollution on COPD in young individuals. Methods We conducted a population-based study of residents aged 15–50 years in the low-income and middle-income regions of western China. We used multivariable logistic regression models to examine the associations between long-term ozone exposure and COPD in young individuals. Results A total of 6537 young cases were identified among the participants, with a COPD prevalence rate of 7.8 (95% CI 7.2% to 8.5%), and most young COPD individuals were asymptomatic. Exposure to household air pollution was associated with COPD in young patients after adjustment for other confounding factors (OR 1.82, 95% CI 1.41 to 2.37). We also found positive associations of COPD with O 3 per IQR increase of 20 ppb (OR 1.92, 95% CI 1.59 to 2.32). The individual effects of household air pollution and O 3 were 1.68 (95% CI 1.18 to 2.46) and 1.55 (95% CI 0.99 to 2.43), respectively, while their joint effect was 3.28 (95% CI 2.35 to 4.69) with the relative excess risk due to interaction of 1.05 (95% CI 0.33 to 1.78). Conclusions This study concludes that exposure to ambient O 3 and household air pollution might be important risk factors for COPD among young adults, and simultaneous exposure to high levels of the two pollutants may intensify their individual effects.
Single‐dose rituximab plus glucocorticoid versus cyclophosphamide plus glucocorticoid in patients with newly diagnosed acquired hemophilia A: A multicenter, open‐label, randomized noninferiority trial
Authors: PanJing Wang, Rongfu Zhou, Feng Xue, Hu Zhou, Jie Bai, Xianghua Wang, Yueshen Ma, Zhen Song, Yunfei Chen, Xiaofan Liu, Rongfeng Fu, Ting Sun, Mankai Ju, Xinyue Dai, Huan Dong, Renchi Yang, Wei Liu, Lei Zhang
Journal: American Journal of Hematology (2023)

Abstract Acquired hemophilia A (AHA) is a rare but serious bleeding disorder. Randomized controlled trial (RCT) comparing the efficacy of immunosuppression therapy for AHA lacks. We conducted the first multicenter RCT aiming to establish whether the single‐dose rituximab combination regimen was noninferior to the cyclophosphamide combination regimen. From 2017 to 2022, 63 patients with newly diagnosed AHA from five centers were randomly assigned 1:1 to receive glucocorticoid (methylprednisolone 0.8 mg/kg per day for the first 3 weeks and then tapered) plus single‐dose rituximab (375 mg/m 2 ; n = 31) or plus cyclophosphamide (2 mg/kg per day until inhibitor becomes negative, for a maximum of 5 weeks; n = 32). The primary outcome was complete remission (CR, defined as FVIII activity ≥50 IU/dL, FVIII inhibitor undetectable, immunosuppression tapered and no bleeding for 24 h without bypassing agents) rate measured within 8 weeks. The noninferiority margin was an absolute difference of 20%. Twenty‐four (77.4%) patients in the rituximab group and 22 (68.8%) patients in the cyclophosphamide group achieved CR, which showed the noninferiority of the single‐dose rituximab‐based regimen (absolute difference = −8.67%, lower limit of the 95% confidence interval = −13.11%; Pnoninferiority = 0.005). No difference was found in the incidence of treatment‐related adverse events. Single‐dose rituximab plus glucocorticoid regimen showed similar efficacy and safety, without a reported risk of secondary malignancies or reproductive toxicity seen in cyclophosphamide, it might be recommended as a first‐line therapy for AHA, especially in China where there is a young age trend in AHA patients. This trial was registered at ClinicalTrials.gov as #NCT03384277.
Switch to oral antibiotics in Gram-negative bacteraemia: a randomized, open-label, clinical trial
Authors: Ali S. Omrani, Sulieman H. Abujarir, Fatma Ben Abid, Shahd H. Shaar, Mesut Yilmaz, Adila Shaukat, Mussad S. Alsamawi, Mohamed S. Elgara, Mohamed Islam Alghazzawi, Khaled M. Shunnar, Ahmed Zaqout, Yasser M. Aldeeb, Wadha Alfouzan, Muna A. Almaslamani, Manaf Alqahtani, Faisal Alshaikh, Mohammad Nazish, Noura Almerdasi, Simin Bangri, Rumeysa Cakmak, Celali Kurt, Arzu Altuncekic Yildirim, Elif Tukenmez-Tigen, Buket Erturk Sengel, Ilker Inanc Balkan, Bilge Çağlar, Mohamed M. Abufaied, Mohsen S. Eledrisi, Hatem Abusriwil, Emad Elmaghboul
Journal: Clinical Microbiology and Infection (2023)

To evaluate the safety and efficacy of switching from intravenous (IV) to oral antimicrobial therapy in patients with Enterobacterales bacteraemia, after completion of 3-5 days of microbiologically active IV therapy.